Researchers have discovered the gene that causes one of the rarest congenital disorders, a disease called FOP that turns muscle and tendons into bone, forming a second skeleton that eventually renders the patient immobile, like a statue.
Fibrodysplasia ossificans progressiva, or FOP, strikes about one in 2 million people -- so rarely that most physicians misdiagnose the disorder, often prescribing treatments that worsen the condition. About 600 patients are known.
The majority of patients become bedridden by their 30s. There is no treatment -- removing the excess bone only makes it grow back faster.
The discovery of the FOP gene could eventually lead to the first treatments for the disease, according to Dr. Frederick S. Kaplan and his colleagues at the University of Pennsylvania School of Medicine.
Their finding, reported Sunday on the website of the journal Nature Genetics, could also lead to new treatments for a variety of other bone diseases that involve either excessive or insufficient bone growth.
"This is a fantastic advance for an absolutely horrible disease," said Dr. Joseph A. Kitterman of UC San Francisco, who was not involved in the research.
FOP is apparent at birth. The patient's big toes, the last segment of the skeleton to form, are unusually short and point outward laterally.
Other symptoms can appear anytime before age 25. The typical first signs are painful swellings on the arm, neck or shoulders. The pain may fade after a few weeks, but the lumps remain.
Mobility progressively decreases. By the teen years, patients usually cannot raise their arms above their heads. As muscles around the lungs convert to bone, breathing becomes more difficult. Trauma, such as bruises, injections and biopsies, accelerate the process.
"This is the only genetic disorder I know of in which one organ is converted into a different one," Kaplan said. "The new bone is totally normal. It is just in the wrong place at the wrong time."
Kitterman, whose step-grandson has the disease, recently surveyed known FOP patients and reported in November in the journal Pediatrics that 87% of them were initially misdiagnosed.
Nearly 50% of them, moreover, received permanent injuries from inappropriate treatment. Kitterman's grandson, like many others, received cancer chemotherapy. Kaplan cited the case of one girl whose arm was amputated because doctors thought she had cancer.
Kaplan has been studying the disorder for 15 years. Over the years, it became clear that the problems were associated with a protein called bone morphogenetic protein, which is known to be linked to bone growth.
But finding the gene was hard because few families have more than one afflicted generation.
Although the gene was known to be autosomal dominant -- meaning that if one parent has it, a child has a 50% chance of inheriting the disease -- most cases involve a spontaneous mutation in the patient at conception.
Ultimately, Kaplan and his colleague Eileen M. Shore assembled five families in which the disease struck at least two generations: two in the United States, one in Bavaria, one in France and one in the Amazon.
In each of the families, they identified a defective form of gene ACVR1, the blueprint for a protein that regulates bone morphogenetic protein.
A change in one nucleotide prevents bone morphogenetic protein from binding properly. The same nucleotide change was subsequently found in virtually all other FOP patients.
"That's all that it takes to subvert all the control mechanisms that have developed over 400 million years of evolution," Kaplan said.
"The importance," he added, "is that this immediately suggests a treatment strategy, although it could be years or decades before an actual treatment is found."
The bone growth in FOP, he noted, is similar to the explosive activity of stem cells in chronic myelogenous leukemia. "We might use something like [the anti-cancer drug] Gleevec, but designed specifically for this receptor."
One patient looking forward to a treatment is 15-year-old Stephanie Snow of Santa Maria, Calif., who has been visiting Kaplan since she was 2. A freshman at Righetti High School, Snow can no longer lift her arms above her shoulders and has impaired mobility in her jaw and hips.
She takes four classes a day at the high school and two more at home, where she raises rabbits and a lamb.
She wants to go to veterinary school at the University of Pennsylvania.
"I didn't think I would see [the gene discovery] this soon," she said. "It has given me a lot of hope."
Her community raised more than $1 million to support Kaplan's research. An annual barbecue served 5,000 meals in two days, and raised $30,000 this year. A formal dinner takes place every August and a Shell gas station owner who donates a penny per gallon has raised $150,000.
"This is a campaign for physical independence and personal freedom for the kids," Kaplan said.
Information obtained from studying ACVR1 could be useful in developing treatments for other diseases.
Excessive bone growth often occurs after hip replacements, head or spinal cord injuries and severe burns, as well as in patients with osteoarthritis.
Insufficient bone growth can occur in patients with osteoporosis, fractures that won't heal or congenital abnormalities of the spine and limbs.